Inconsistency in steroid use as antiemetics in clinical trial protocols involving immune checkpoint inhibitors combined with chemotherapy

Abstract Objectives This study aims to investigate the use of steroids as antiemetics in clinical trials involving immune checkpoint inhibitors with chemotherapy. Methods Focusing on phase III trials registered before August 2023, it evaluated the consistency of steroid use guidelines. Results Out of 3452 trials screened, 44 were selected for in‐depth review. The findings indicate a considerable variation: 13 trials did not specify the use of antiemetics, while 31 provided criteria for antiemetics, with 13 conforming to local standards, six to international guidelines, and five allowing either. Seven trials recommended effective antiemetics without detailed criteria. This inconsistency led to a range of steroid dosages, with only 11 trials advocating for minimizing or avoiding steroids for antiemetic purposes. Conclusion The research highlights the lack of uniformity in antiemetic steroid use in trials, reflecting diverse clinical practices and underscoring the need for further research to understand the implications on treatment outcomes.

may influence the efficacy of ICIs, 3 while also playing a complex role in managing cancer-and chemotherapyrelated symptoms. 4he cancer treatment landscape with ICIs is shifting from monotherapy to combination with other anticancer agents. 5This shift demands a deeper look into the necessary use of steroids.The use of corticosteroids, while not essential for ICI monotherapy, are often necessary in ICIchemotherapy combinations.For instances, taxane treatments involve two 20 mg doses for paclitaxel and three 16 mg doses for docetaxel, addressing hypersensitivity and edema. 6Platinum-based chemotherapies necessitate 8-12 mg of dexamethasone over 3-4 days to prevent nausea and vomiting. 7lthough numerous studies have explored the effect of steroids on ICI treatment outcomes, 4,[8][9][10][11] most have focused on ICI monotherapy.Steroids generally have a negative effect on the efficacy of immunotherapies, influenced by factors such as the timing and purpose of administration. 12Research on the use of steroids as a prophylactic measure, particularly as antiemetics, remains limited.Given their immunosuppressive nature, the potential influence of steroids on ICI effectiveness, even temporary use, needs more investigation.This study systematically reviewed antiemetic steroid use in clinical trial protocols for ICIs combined with chemotherapy, a critical step towards aligning research outcomes with clinical practice.

| METHODS
This review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. 13It involved a comprehensive analysis of clinical trials involving ICIs in combination with parenteral anticancer agents with moderate to high emetogenic risk, specifically focusing on recommending steroid use as an antiemetic.The evaluated ICIs included programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors approved by the Food and Drug Administration (FDA), such as atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, nivolumab, and pembrolizumab.The emetogenic potential of anticancer agents was determined based on the guidelines provided by the National Comprehensive Cancer Network (NCCN). 7 detailed electronic search on clini caltr ials.gov used keywords like "combination," "combinations," "combined," and "chemotherapy" along with the specific names of ICIs, limited to studies posted until August 31, 2023.Exclusions were made for indeterminate phase or phase 4 studies and those involving children under 17 years.
Our review process involved scrutinizing the titles and detailed descriptions of the retrieved trials.Eligible studies were defined as: (1) phase III clinical trials, (2) trials conducted with adult participants, (3) trials investigating a combination of ICIs and systemic chemotherapy, and (4) trials incorporating parenteral anticancer drugs with moderate-to-high emetogenic potential.Trials without accessible research protocols, either through clini caltr ials.gov or their publications, were excluded.
The analysis included reviewing cancer indications and types of anticancer agents used in the combination regimen.We carefully extracted and assessed all pertinent data pertaining to patient inclusion and exclusion criteria related to steroid use and the administration of antiemetics, including steroids.Specifically, regarding the use of antiemetic steroids, we thoroughly reviewed and categorized study protocols that provided explicit instructions for their use or placed restrictions on their use.

| RESULTS
The initial database search across various ICIs resulted in 3452 trials (Figure S1).Refining to phase III trials of ICIs with systemic chemotherapy in adults reduced the trials to 296, and after removing duplicates to 276 trials.Of these, 147 trials specifically focused on combination with moderate-to-high emetogenic chemotherapy.Limited availability of detailed protocols led to excluding 103 trials.Consequently, 44 trials were included in the analysis.
In these 44 trials, pembrolizumab emerged as the most investigated ICI and was featured in 15 studies.Lung cancer was the predominant cancer type in 21 studies.The combination therapies employed in these trials universally involved parenteral cytotoxic anticancer agents, with 41 of 44 trials including regimens with a high emetogenic risk (Table 1).
Focusing on the criteria for antiemetic medication use, we found that 13 trials (29.5%) of the 44 trials did not specify the use of antiemetics but allowed temporary use of steroids, whereas 31 trials (70.5%) delineated criteria for antiemetic steroid use (Table 2).Of the latter, 13 trials (29.5%) recommended following local standards for antiemetic use, and of these, five (11.4%) also suggested compliance with the manufacturer's instructions.Eleven studies (25.0%) adhered to international guidelines, and of these, five studies (11.4%) allowed the use of either local or international standards.These guidelines for antiemetics varied in their sources, including the Multinational Association of Supportive Care in Cancer (MASCC) in five studies, NCCN in four studies, the American Society of Clinical Oncology (ASCO) in one study, and a choice between NCCN and ASCO in another.The steroid dosages used in these guidelines are summarized in Table S1.Additionally, the remaining seven (15.9%) of 31 studies underlined the importance of effective antiemetic agents without specifying precise criteria.
The study protocols lacked specific information on the use and dosage of steroids for the local standards, and there were discrepancies in the criteria for antiemetics as outlined in several international guidelines.Notably, only 11 trials (25.0%) suggested either minimizing or avoiding steroids for antiemetic purposes.Detailed criteria for steroid use in each study protocol are listed in Table S2.

| DISCUSSION
This investigation underscores the absence of uniform guidelines for steroid use as an antiemetic in clinical trial protocols exploring the combination of ICIs with conventional chemotherapy.A key challenge encountered was determining the precise dosage and duration of steroid administration as most trials followed individual institutional guidelines which varied considerably.This variability was further complicated by differing international guidelines for antiemetic use.For instance, although the NCCN classifies carboplatin doses of AUC 4 or higher as high risk, 7 ASCO and MASCC consider them as moderate risk. 14,15This disparity in emetogenic risk assessment likely leads to diverse practices in steroid usage for emesis prevention, especially as 31 of the 44 analyzed trials involved carboplatin in combination therapy.
Steroid administration in the context of ICI treatment occurs under various scenarios: chronic use for pre-existing conditions, management of immune-related adverse effects from ICIs, or preventive measures against chemotherapy-induced emesis. 16Previous studies have shown that baseline steroid use exceeding 10 mg of prednisolone may lead to poor outcomes in ICI treatments. 17ur analysis indicates that clinical trial protocols consistently required discontinuing steroid use 1-2 weeks before starting the study.Interestingly, using steroids to manage serious immune-related adverse effects does not appear to negatively affect the efficacy of ICI treatments, 4 and clinical trial protocols universally recommend their use for severe immune-related adverse effects.
The consistent outline in study protocols for using steroids for these purposes poses challenges in further limiting steroid use.The impact of antiemetic steroids, the primary focus of this study, remains controversial.However, few prospective studies have evaluated the effect of short-term steroid use on the effectiveness of ICIs.A preclinical study indicates that dexamethasone can significantly reduce the antitumor response in ICI and chemotherapy combinations, 18 with similar observations in non-small cell lung cancer (NSCLC) patients receiving ICI monotherapy, suggesting that early steroid use may diminish the efficacy of ICIs. 19While a meta-analysis highlighted the negative impact of steroids on survival, specific effects as antiemetics, dosage, and duration were not detailed, 20 and a study in non-squamous NSCLC showed that antiemetic steroids did not significantly impact survival, albeit with a small sample size. 21Given that chemotherapy is generally recommended only in the early stages of combination therapy, dexamethasone administered as a premedication for chemotherapy could potentially compromise the effectiveness of ICIs.
A recently published ASCO guideline indicated that there is insufficient clinical evidence to advise against dexamethasone in antiemetic regimens for patients undergoing ICI and chemotherapy, as studies like KEYNOTE-189 and KEYNOTE-407 have shown a survival benefit despite the use of potent antiemetic steroids. 14 Clinical trial characteristics (N = 44).
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